Inhibition of the complement component C5 and the Toll-like receptor molecule CD14 prevents systemic and local kidney inflammation in mice experiencing brain death
Abstract Brain death (BD) induces a systemic inflammation impairing donor organ quality. Complement and Toll-like receptors (TLRs), with the key co-receptor CD14 molecule, are key innate recognition immune systems. We hypothesized that dual inhibition of complement (C5) and TLRs (CD14) will prevent...
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Nature Portfolio
2025-07-01
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| Online Access: | https://doi.org/10.1038/s41598-025-12071-x |
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| author | Tom E. Mollnes Neeltina M. Jager Petra J. Ottens Camilla Schjalm Zwanida J. Veldhuis Henri G. D. Leuvenink Søren E. Pischke |
| author_facet | Tom E. Mollnes Neeltina M. Jager Petra J. Ottens Camilla Schjalm Zwanida J. Veldhuis Henri G. D. Leuvenink Søren E. Pischke |
| author_sort | Tom E. Mollnes |
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| description | Abstract Brain death (BD) induces a systemic inflammation impairing donor organ quality. Complement and Toll-like receptors (TLRs), with the key co-receptor CD14 molecule, are key innate recognition immune systems. We hypothesized that dual inhibition of complement (C5) and TLRs (CD14) will prevent BD-mediated innate immune inflammation. BD was induced in mice either untreated, treated with a C5 inhibitor, a CD14 inhibitor, or both. Blood and kidneys were collected after three hours. Cytokines were analyzed using enzyme-immuno assays and qPCR. In plasma, a substantial increase in interleukin-6 (IL-6), KC (IL-8 analogue), IL-12, monocyte chemoattractant protein (MCP-1), macrophage inflammatory protein MIP-1α, MIP-1β, eotaxin, RANTES and G-CSF (median 90-fold increase) were observed in BD animals compared to sham (all p < 0.01). In kidneys, BD substantially induced IL-6, KC, TNF, MCP-1, P-Selectin, and VCAM-1 (all p < 0.01). In plasma, C5 and CD14 inhibition, either single or in combination, virtually abolished all cytokines in the BD animals (> 90% for six cytokines and 70–90% for three) (all p < 0.01). In kidneys, the effect of inhibition was similar (> 90% for IL-6 and KC and 60–80% for TNF and MCP-1 (all p < 0.01). Single and combined inhibition of C5 and CD14 efficiently prevented BD-induced systemic inflammation and reduced local kidney inflammation in a mouse model. |
| format | Article |
| id | doaj-art-5329afc2632345c19aa174c8dcb7a86c |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-5329afc2632345c19aa174c8dcb7a86c2025-08-20T03:45:52ZengNature PortfolioScientific Reports2045-23222025-07-0115111210.1038/s41598-025-12071-xInhibition of the complement component C5 and the Toll-like receptor molecule CD14 prevents systemic and local kidney inflammation in mice experiencing brain deathTom E. Mollnes0Neeltina M. Jager1Petra J. Ottens2Camilla Schjalm3Zwanida J. Veldhuis4Henri G. D. Leuvenink5Søren E. Pischke6Department of Immunology, Oslo University Hospital and University of OsloDepartment of Anesthesiology, University of Groningen, University Medical Center GroningenDepartment of Surgery, University of Groningen, University Medical Center GroningenDepartment of Immunology, Oslo University Hospital and University of OsloDepartment of Surgery, University of Groningen, University Medical Center GroningenDepartment of Surgery, University of Groningen, University Medical Center GroningenDepartment of Immunology, Oslo University Hospital and University of OsloAbstract Brain death (BD) induces a systemic inflammation impairing donor organ quality. Complement and Toll-like receptors (TLRs), with the key co-receptor CD14 molecule, are key innate recognition immune systems. We hypothesized that dual inhibition of complement (C5) and TLRs (CD14) will prevent BD-mediated innate immune inflammation. BD was induced in mice either untreated, treated with a C5 inhibitor, a CD14 inhibitor, or both. Blood and kidneys were collected after three hours. Cytokines were analyzed using enzyme-immuno assays and qPCR. In plasma, a substantial increase in interleukin-6 (IL-6), KC (IL-8 analogue), IL-12, monocyte chemoattractant protein (MCP-1), macrophage inflammatory protein MIP-1α, MIP-1β, eotaxin, RANTES and G-CSF (median 90-fold increase) were observed in BD animals compared to sham (all p < 0.01). In kidneys, BD substantially induced IL-6, KC, TNF, MCP-1, P-Selectin, and VCAM-1 (all p < 0.01). In plasma, C5 and CD14 inhibition, either single or in combination, virtually abolished all cytokines in the BD animals (> 90% for six cytokines and 70–90% for three) (all p < 0.01). In kidneys, the effect of inhibition was similar (> 90% for IL-6 and KC and 60–80% for TNF and MCP-1 (all p < 0.01). Single and combined inhibition of C5 and CD14 efficiently prevented BD-induced systemic inflammation and reduced local kidney inflammation in a mouse model.https://doi.org/10.1038/s41598-025-12071-xBrain deathDonorInflammationComplementCD14Kidney |
| spellingShingle | Tom E. Mollnes Neeltina M. Jager Petra J. Ottens Camilla Schjalm Zwanida J. Veldhuis Henri G. D. Leuvenink Søren E. Pischke Inhibition of the complement component C5 and the Toll-like receptor molecule CD14 prevents systemic and local kidney inflammation in mice experiencing brain death Scientific Reports Brain death Donor Inflammation Complement CD14 Kidney |
| title | Inhibition of the complement component C5 and the Toll-like receptor molecule CD14 prevents systemic and local kidney inflammation in mice experiencing brain death |
| title_full | Inhibition of the complement component C5 and the Toll-like receptor molecule CD14 prevents systemic and local kidney inflammation in mice experiencing brain death |
| title_fullStr | Inhibition of the complement component C5 and the Toll-like receptor molecule CD14 prevents systemic and local kidney inflammation in mice experiencing brain death |
| title_full_unstemmed | Inhibition of the complement component C5 and the Toll-like receptor molecule CD14 prevents systemic and local kidney inflammation in mice experiencing brain death |
| title_short | Inhibition of the complement component C5 and the Toll-like receptor molecule CD14 prevents systemic and local kidney inflammation in mice experiencing brain death |
| title_sort | inhibition of the complement component c5 and the toll like receptor molecule cd14 prevents systemic and local kidney inflammation in mice experiencing brain death |
| topic | Brain death Donor Inflammation Complement CD14 Kidney |
| url | https://doi.org/10.1038/s41598-025-12071-x |
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